Timed NAD+ boosting in the early morning will reinforce circadian amplitude and counteract age‑related melatonin loss. The hypothesis rests on two well‑established links: NAD+ fuels SIRT1 deacetylase activity, and SIRT1 directly stabilizes the core clock by deacetylating BMAL1 and PER2, thereby enhancing transcriptional oscillations Clock genes intersect with SIRT1 and FOXO3 longevity pathways. Stronger clock drives higher expression of NAMPT, the enzyme that salvages NAD+, creating a feed‑forward loop that raises cellular NAD+ levels specifically during the subjective day. Elevated NAD+ also fuels PARP‑mediated DNA repair in the suprachiasmatic nucleus, reducing oxidative lesions that otherwise blunt SCN firing Circadian disruption accelerates aging via oxidative stress and DNA damage. Because melatonin synthesis in the pineal gland depends on a robust circadian signal from the SCN, amplifying clock output should restore the youthful night‑time melatonin peak that declines with age.

We predict that a single dose of nicotinamide riboside (NR) administered at 08:00 h will increase melatonin amplitude by ≥20 % after four weeks, lengthen leukocyte telomere attrition rate by <10 % per year, lower high‑sensitivity CRP by ≥15 %, and improve composite cognitive scores by ≥0.3 SD versus placebo. A parallel arm receiving only morning bright‑light therapy (as shown to shift phase and add sleep) will serve to isolate the NAD+‑specific effect Optimized lighting improves sleep in shift workers. A third arm combining NR with morning light will test for additive benefits. All participants will wear actigraphs to verify sleep timing and duration, ensuring that any observed differences are not merely due to changes in sleep length.

Mechanistically, we anticipate that heightened SIRT1 activity will also deacetylate FOXO3, promoting its nuclear translocation and up‑regulation of autophagy genes, thereby clearing damaged mitochondria in neurons and immune cells. Improved autophagy should further reduce inflammasome activation, contributing to the expected CRP drop. Additionally, increased NAD+ will support sirtuin‑dependent deacetylation of PGC‑1α, boosting mitochondrial biogenesis and reinforcing the metabolic rhythms that reinforce clock gene expression.

If the NAD+ group fails to show significant improvements in any of these pre‑specified outcomes, the hypothesis is falsified. Conversely, confirming the predicted changes would demonstrate that bolstering the NAD+‑SIRT1 clock axis is a mechanistic lever that can extend healthspan beyond what sleep duration alone achieves, offering a testable, chronobiology‑based intervention for aging populations.